CAMBRIDGE, Mass.--Researchers from MIT's Picower Institute for Learning and Memory have uncovered a molecular mechanism that governs the formation of fears stemming from traumatic events. The work could lead to the first drug to treat the millions of adults who suffer each year from persistent, debilitating fears - including hundreds of soldiers returning from conflict in Iraq and Afghanistan.
A treatment for post traumatic stress disorder and other learned fears would help a lot of people.
Kinase enzymes attach phosphate groups onto proteins and this gets used in cells to regulate many aspects of cellular activity. Inhibition of a kinase called Cdk5 undoes a learned fear response.
Li-Huei Tsai, Picower Professor of Neuroscience in the Department of Brain and Cognitive Sciences, and colleagues show that inhibiting a kinase (kinases are enzymes that change proteins) called Cdk5 facilitates the extinction of fear learned in a particular context. Conversely, the learned fear persisted when the kinase's activity was increased in the hippocampus, the brain's center for storing memories.
Cdk5, paired with the protein p35, helps new brain cells, or neurons, form and migrate to their correct positions during early brain development. In the current work, the MIT researchers looked at how Cdk5 affects the ability to form and eliminate fear-related memories.
"Remarkably, inhibiting Cdk5 facilitated extinction of learned fear in mice. This data points to a promising therapeutic avenue to treat emotional disorders and raises hope for patients suffering from post-traumatic stress disorder or phobia," Tsai said.
I wonder if the Cdk5 inhibitor just extinguishes the fear response to the original memory or does it wipe out the original memory?
While existing antidepressants such as Zoloft, Prozac, and Paxil take weeks to begin working ketamine starts lifting mood within 2 hours.
People with treatment-resistant depression experienced symptom relief in as little as two hours with a single intravenous dose of ketamine, a medication usually used in higher doses as an anesthetic in humans and animals, in a preliminary study. Current antidepressants routinely take eight weeks or more to exert their effect in treatment-resistant patients and four to six weeks in more responsive patients — a major drawback of these medications. Some participants in this study, who previously had tried an average of six medications without relief, continued to show benefits over the next seven days after just a single dose of the experimental treatment, according to researchers conducting the study at the National Institutes of Health's National Institute of Mental Health.
This is among the first studies of humans to examine the effects of ketamine on depression, a debilitating illness that affects 14.8 million people in any given year. Used in very low doses, the medication is important for research, but is unlikely to become a widely used clinical treatment for depression because of potential side effects, including hallucinations and euphoria, at higher doses. However, scientists say this research could point the way toward development of a new class of faster- and -longer-acting medications. None of the patients in this study, all of whom received a low dose, had serious side effects. Study results were published in the August issue of the Archives of General Psychiatry.
Imagine living in perpetual depression. What a hell. Though some readers do not have to imagine. You have my sympathy.
The effect is quick and dramatic.
For this study 18 treatment-resistant, depressed patients were randomly assigned to receive either a single intravenous dose of ketamine or a placebo (inactive compound). Depression improved within one day in 71 percent of all those who received ketamine, and 29 percent of these patients became nearly symptom-free within one day. Thirty-five percent of patients who received ketamine still showed benefits seven days later. Participants receiving a placebo infusion showed no improvement. One week later, participants were given the opposite treatment, unless the beneficial effects of the first treatment were still evident. This "crossover" study design strengthens the validity of the results.
"To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients," said NIMH Director Thomas R. Insel, M.D.
Receptors for the neurotransmitter glutamate are blocked by ketamine and glutamate regulation appears to play an key role in causing depression.
Ketamine blocks a brain protein called the N-methyl-D-aspartic acid (NMDA) receptor. Previous studies have shown that agents that block the NMDA receptor reduce depression-like behaviors in animals.
NMDA receptors are critical for receiving the signals of glutamate, a brain chemical that enhances the electrical flow among brain cells that is required for normal function. Studies indicate that dysregulation in glutamate could be among the culprits in depression. Using ketamine to block glutamate's actions on the NMDA receptor appears to improve function of another brain receptor — the AMPA receptor — that also helps regulate brain cells' electrical flow.
This result is another clue. Eventually depression will become completely curable and preventable.
Other anti-depressants probably take longer because they act at the beginning of a long chain of causation.
Scientists think the reason current antidepressant medications take weeks to work is that they act on targets close to the beginning of a series of biochemical reactions that regulate mood. The medications' effects then have to trickle down through the rest of the reactions, which takes time. Scientists theorize that ketamine skips much of this route because its target, the NMDA receptor, is closer to the end of the series of reactions in question.
Given that ketamine acts way downstream closer to the final effect of depression it or similarly acting compounds (preferably with fewer side effects) could lift depression while the longer acting compounds build up their effects. For people with severe depression hospitalization or administration of ketamine in clinics might be worth it.
Ravers in settings where people use ecstasy and looking for a new kind of kick have labelled ketamine "Special K" and used it in higher doses. But ketamine has very different effects including paralysis.
At low doses the user may feel euphoric, experience waves of energy, and possibly synaesthesia - sensations such as seeing sounds or hearing colours.
At higher doses the user might become paralysed, experience hallucinations and alternate realities, and a feeling of disassociation giving an 'out of body' experience known as the "K-hole".
Not for casual use.
If you are curious check out the Wikipedia entry on ketamine.
Update: Note that ketamine works for people who fail to get benefit from currently approved anti-depressants. Those who aren't helped by existing anti-depressants probably have tried Selective Serotonin Update Inhibitors (SSRIs) such as Prozac and Zoloft. Well, this result suggests that there are points in the chain of causation where depression can get initiated that are downstream of serotonin receptors and yet upstream of the glutamate receptors. SSRIs won't work with people whose depression gets initiated downstream of serotonin receptors.
Intervention with ketamine might make sense for those people who get no benefit from SSRIs. But ketamine is probably not ideal for them. In most cases the best treatment should act at the earliest stage in the series of events that cause a person to get depressed. Depression has multiple causes. The earliest stage will be different for each different cause.
A team including Michael Kosfeld and Ernst Fehr at the University of Zurich and oxytocin researcher Paul Zak at have found that oxytocin nasal spray makes people more trusting.
A Swiss-led research team tested their creation on volunteers playing an investment game for real money. When they inhaled the nasal spray, investors were more likely to hand over money to a trustee, knowing that, although they could make a hefty profit, they could also lose everything if the trustee decided not to give any of the money back.
The potion's magic ingredient is oxytocin, a chemical that is produced naturally in the brain. Its production is triggered by a range of stimuli, including sex and breastfeeding, and it is known to be important in the formation of social ties, such as mating pairs and parent-offspring bonds. It is perhaps no surprise that the compound has been nicknamed the 'love hormone'.
Note: Oxytocin is not the painkiller oxycontin.
Oxytocin decreases the anxiety people feel toward strangers.
"If I increase your level of oxytocin, I can induce you to overcome your anxiety in trusting a stranger," said Paul J. Zak, director of Claremont's center for neuroeconomic studies and a co-author of the research paper. "It is a [biochemical] signal we induce unknowingly all the time by looking people in the eye or shaking someone by the hand."
The effect of nasally administered oxytocin peaks in about 50 minutes and wears off about 2 hours after administration.
Oxytocin might be useful for overcoming shyness.
Neuroscientists, including the Swiss researchers, argue that oxytocin is not so much a trust serum as a kind of brain messenger that primes animals to overcome their natural aversion to others. It allows for what they call "approach behavior," that push to walk up and to a stranger and say hello.
This may be an especially important ability in people with autism. Whether oxytocin or other hormones could affect such behavior is unclear, but the oxytocin study suggests it is worth investigating.
If oxytocin turns out to benefit the painfully shy people then it is not hard to imagine many shy people electing to use it on themselves before entering social situations.
The scientists were not expecting this result.
Paradoxically, Dr Fehr and his colleagues began the experiment because one of them believed that oxytocin signalled trustworthiness, rather than a propensity to trust.
Oxytocin has been facilitatng mating for 100 million years.
The discovery is the first direct evidence that a hormone called oxytocin, which evolved 100 million years ago to aid mating among fish and breast-feeding among mammals, also promotes trust between human beings, the scientists said.
Imagine oxytocin or another more potent compound delivered at political rallies.
"Some may worry about the prospect that political operators will generously spray the crowd with oxytocin at rallies of their candidates," said neurologist Antonio R. Damasio of the University of Iowa, who has long studied the neurobiology of human emotions and who wrote a commentary accompanying the study.
At the same time, he added in an interview, politicians and marketers were probably already triggering the natural release of oxytocin in the brains of audiences through their campaigns. "I am more alarmed about the manipulations of marketing than the possibility of oxytocin sprays," he said.
Even if someone could spray a crowd at a political rally with an effective dose would the feeling of trust last beyond the point where the oxytocin wears off? Would an argument made to a person in a highly trusting state have more effect afterward than one made to a person in a more skeptical state of mind? My guess is yes.
How about a compond made to work like oxytocin which has a much longer half life? Such a compound would be effective when used in fanatical sects when indoctrinating new recruits.
The development of oxytocin blockers might be possible. Oxytocin could be used by people who frequently find themselves to be excessively trusting and who therefore often find themselves victimized by agreeing to deals with swindlers and manipulators. Entire populations might want to take oxytocin blockers during political campaigns or when going into environments which expose people to large amounts of advertising.
Oxytocin might be a useful tool in interrogations of terrorists. By engendering trust it might be a useful component in a truth serum. On the other hand, slow release and long half life oxytocin blockers embedded in a person's body could be used by spies and others at risk of capture and prolonged interrogation.
This study is part of a general trend: The moods and motivations of the human mind are becoming more susceptible to biochemical alteration. Oxytocin joins Valium, Prozac, Zoloft, Paxil, and a long list of other drugs which alter moods. Accumulating discoveries about how the mind works lead inevitably to the development of new drugs and, in the future, even gene therapies that alter emotions, motivations, and circuitry that delivers rewards. Arguments for the existence of free will are hard to square with scientific advances which show how to bend the will.
The future is going to be a very different place. We live on the verge of an age of genetically engineered emotion and motivation alteration.
Using a new molecular genetic technique, scientists have turned procrastinating primates into workaholics by temporarily suppressing a gene in a brain circuit involved in reward learning. Without the gene, the monkeys lost their sense of balance between reward and the work required to get it, say researchers at the NIH's National Institute of Mental Health (NIMH).
"The gene makes a receptor for a key brain messenger chemical, dopamine," explained Barry Richmond, M.D., NIMH Laboratory of Neuropsychology. "The gene knockdown triggered a remarkable transformation in the simian work ethic. Like many of us, monkeys normally slack off initially in working toward a distant goal. They work more efficiently – make fewer errors – as they get closer to being rewarded. But without the dopamine receptor, they consistently stayed on-task and made few errors, because they could no longer learn to use visual cues to predict how their work was going to get them a reward."
Richmond, Zheng Liu, Ph.D., Edward Ginns, M.D., and colleagues, report on their findings in the August 17, 2004 Proceedings of the National Academy of Sciences, published online the week of August 9th.
Richmond's team trained monkeys to release a lever when a spot on a computer screen turned from red to green. The animals knew they had performed the task correctly when the spot turned blue. A visual cue--a gray bar on the screen--got brighter as they progressed through a succession of trials required to get a juice treat. Though never punished, the monkeys couldn't graduate to the next level until they had successfully completed the current trial.
As in a previous study using the same task, the monkeys made progressively fewer errors with each trial as the reward approached, with the fewest occurring during the rewarded trial. Previous studies had also traced the monkeys' ability to associate the visual cues with the reward to the rhinal cortex, which is rich in dopamine. There was also reason to suspect that the dopamine D2 receptor in this area might be critical for reward learning. To find out, the researchers needed a way to temporarily knock it out of action.
They used DNA antisense oligonucleotides which are short stretches of DNA sequence which match with a target gene to bind to it to prevent ts expression.
Molecular geneticist Ginns, who recently moved from NIMH to the University of Massachusetts, adapted an approach originally used in mice. He fashioned an agent (DNA antisense expression construct) that, when injected directly into the rhinal cortex of four trained monkeys, spawned a kind of decoy molecule which tricked cells there into turning-off D2 expression for several weeks. This depleted the area of D2 receptors, impairing the monkeys' reward learning. For a few months, the monkeys were unable to associate the visual cues with the workload – to learn how many trials needed to be completed to get the reward.
Monkeys are usually procrastinators. But the lack of D2 receptors turned them into workaholics.
"The monkeys became extreme workaholics, as evidenced by a sustained low rate of errors in performing the experimental task, irrespective of how distant the reward might be," said Richmond. "This was conspicuously out-of-character for these animals. Like people, they tend to procrastinate when they know they will have to do more work before getting a reward."
Using the same technique to turn off NMDA receptors did to increase motive to work for a reward.
To make sure that it was, indeed, the lack of D2 receptors that was causing the observed effect, the researchers played a similar recombinant decoy trick targeted at the gene that codes for receptors for another neurotransmitter abundant in the rhinal cortex: NMDA (N-methlD-aspartate). Three monkeys lacking the NMDA receptor in the rhinal cortex showed no impairment in reward learning, confirming that the D2 receptor is critical for learning that cues are related to reward prediction. The researchers also confirmed that the DNA treatments actually affected the targeted receptors by measuring receptor binding following the intervention in two other monkeys' brains.
And you can bet these researchers are thinking about how to use this technique on people.
"This new technique permits researchers to, in effect, measure the effects of a long-term, yet reversible, lesion of a single molecular mechanism," said Richmond. "This could lead to important discoveries that impact public health. In this case, it's worth noting that the ability to associate work with reward is disturbed in mental disorders, including schizophrenia, mood disorders and obsessive-compulsive disorder, so our finding of the pivotal role played by this gene and circuit may be of clinical interest," suggested Richmond.
"For example, people who are depressed often feel nothing is worth the work. People with OCD work incessantly; even when they get rewarded they feel they must repeat the task. In mania, people will work feverishly for rewards that aren't worth the trouble to most of us."
Of course there is the classical science fiction threat of companies or governments taking over the minds of people to train them to work hard for the organization. The classical abuses will probably happen eventually and may lead to some pretty horrible outcomes. But I can easily imagine why lots of people (FuturePundit included) will choose to use drugs to motivate themselves. Looking at a big long work task? Know that you are hurting yourself by not working harder during the earlier stages? Well, take some DNA antisense drug and as your D2 receptor concentration drops you may find yourself working harder for distant rewards.
The problems with delivering DNA antisense oligonucleotides into cells will be solved in time as part of the larger push to develop techniques to deliver gene therapy into cells. Once the delivery vehicles are available the use of gene therapy will allowing temporary and permanent modification of personality, emotional state, and behavior on a scale that will make Prozac and Zoloft seem like primitive tools in comparison.
Update: And what about the economic impact of motivation enhancing gene therapy? While I'm bearish about the next 20 or 30 years due to aging populations and other demographic problems once we can raise IQ, increase motivation, and do other cognitive tweaking it is hard to see how economic output will not be greatly increased. Raising IQ is going to be harder to do than motivation alteration. But just reducing the amount of procrastination would be a big boost to productivity. Add in rejuvenation therapies, IQ enhancement of progeny (which will be easier to do than IQ enhancement of adutls), and even cognitive enhancement of adults and in a longer time frame the human part of the economic productivity equation looks much rosier. What is harder to predict is just when the these various capabilities will be available.
Update II: Note that the level of motivation varies greatly from one person to the next. Also, some people are better set up to pursue longer term goals and others need more immediate rewards to get off their duffs and do anything. This latest result suggests a possible reason: differing levels of expression of genes that control dopamine D2 receptor concentrations. Once offspring genetic engineering becomes possible will people opt to have children who are more motivated than they are? Also, will employers surreptitiously take samples of DNA from job applicants to decide which applicants will be the hardest workers? Will some applicants even go so far as to state that while their natural DNA sequences tend to make them slackers and procrastinators they have permanently altered their personalities to turn themselves into workaholic maniacs? Will applicants even supply suitably certified medical records as evidence of their altered state? It all seems very plausible to me...
Mark A. Mintun, M.D., professor of radiology and of psychiatry at Washington University School of Medicinem and colleagues have found that depressed people have fewer 5-HT2A serotonin receptors.
To get a look at how the brain works differently in depressed patients, Mintun and colleagues studied 46 people with active depression and compared positron emission tomography (PET) scans of their brains to scans from 29 people who were not depressed. The team was measuring levels of a particular type of serotonin receptor called the 5-HT2A serotonin receptor.
Mintun has been on the trail of serotonin receptors for years. "The 5-HT2A receptor in this study is the most common of several types of serotonin receptors, so we thought this would be a good place to start," he says.
Almost a decade ago at the University of Pittsburgh, Mintun and radiochemist Chester Mathis, Ph.D., developed a method of labeling the 5-HT2A serotonin receptor with a chemical called altanserin. The altanserin sticks to the serotonin receptors and allows the PET scanner to take pictures of them.
Because most people with depression get better when their serotonin levels increase after treatment with SSRIs, Mintun initially believed the PET scans would reveal high levels of serotonin receptors in brain structures linked to depression. The hypothesis was that because less serotonin was available, the brain would try to compensate by making more receptors.
But that's not what they found. In the February issue of the journal Biological Psychiatry, Mintun and colleagues report that the depressed people actually had fewer serotonin receptors throughout the brain and significantly fewer receptors in a key structure called the hippocampus, an area that acts as a gateway between memory and mood, among other processes.
Anti-depressant drugs seem to protect the hippocampus and make it bigger.
Meanwhile, in a parallel series of depression studies, co-author Yvette I. Sheline, M.D., associate professor of psychiatry, radiology and neurology, was learning from magnetic resonance imaging (MRI) scans of depressed patients that the hippocampus is smaller in patients with depression. Sheline also has found that antidepressant drugs seem to have a protective effect and prevent some of the volume loss she has observed.
Putting it all together, Sheline says the volume loss in the hippocampus might be to blame for the low number of serotonin receptors, rather than the other way around.
"Although it's clear that serotonin is involved in depression, it may be that the volume loss we have observed is due to damage in cells in the hippocampus, which then cannot process serotonin effectively," Sheline says. "Perhaps the low number of serotonin receptors is related to cell damage in the hippocampus rather than the damage and volume loss being caused by problems in the serotonin system."
A longitudinal study started with a population that is not depressed and then followed hippocampus size at the onset of depression and after an extended period of being depressed would go a long way in answering the question of what comes first and causes depression and what changes are a consequence rather than causes of depression.
The anti-depressant drugs known as selective serotonin reuptake inhibitors (SSRIs) such as Zoloft (sertraline), Paxil (Paroxetine), and Prozac (fluoxetine) are known to take a few weeks to cause a beneficial effect and also we know that only after taking them a few weeks hippocampal stem cell division is increased. So it might be that taking them leads to an increase in neuron formation for neurons that have serotonin receptors and that part of the benefit of the SSRIs is that they increase the number of serotonin receptors by causing neural stem cell division.
This report is another indication that depression is gradually being figured out piece by piece. We will some day reach the point where depression becomes reliably curable in the vast bulk of the populace with treatments that have little or no side effects. Given that the rate of advance of biological science and biotechnology are accelerating my guess is that depression will be curable for the vast bulk of the population within an absolute maximum of 30 years and probably more like 20 years.
Also check out some of my other serotonin-related posts: Serotonin Transporter Gene Linked To Depression, Binge Drinking, Serotonin Receptor Concentration Varies Inversely With Spirituality, Excess Serotonin 5-HT1A Receptor Increases Depression, Suicide, Serotonin Receptor Concentration Correlates With Anxiety , and Serotonin Receptor Variation Causes Worse Short Term Memory.
People who are plagued by irrational crippling fears have new hope. An extract of yohimbe tree bark helps mice adjust to and overcome fear four times faster than controls.
New findings at the UCLA Neuropsychiatric Institute demonstrate the potential of a substance found in yohimbe tree bark to accelerate recovery from anxiety disorders suffered by millions of Americans.
In the latest in a series of studies of how mice acquire, express and extinguish conditioned fear, the UCLA team finds yohimbine helps mice learn to overcome the fear faster by enhancing the effects of the natural release of adrenaline. Adrenaline prompts physiological changes such as increased heart and metabolism rates in response to physical and mental stress.
Writing in the March/April edition of the peer-reviewed journal Learning and Memory, the team reported that mice treated with yohimbine overcame their fear four times as fast as those treated with vehicle or propanolol, a medication commonly used to treat symptoms of anxiety disorders by blunting the physiological effects of adrenaline.
Yohimbine is most commonly used to treat erectile dysfunction. It can cause anxiety in susceptible persons, and should never be used without a doctor’s recommendation and supervision.
This is yet another small step down the road toward the eventual achievement of total control of emotional reactions. Some day it will become possible to adjust one's brain to have emotional reactions highly customized for any of a variety of desired purpose. It will become possible, for instance, to adjust emotional reactions to focus one's attentions and energies to achieve ambitious goals or to adjust one's reactions to make it easier to bear situations one can not escape from.
One big open question about this trend for the future is whether people will tend to choose emotional response patterns that make humanity more or less civilized and more or less likely to destroy ourselves.